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Inhibition of transglutaminase 2 mitigates transcriptional dysregulation in models of Huntington disease

  • Author(s): McConoughey, Stephen J
  • Basso, Manuela
  • Niatsetskaya, Zoya V
  • Sleiman, Sama F
  • Smirnova, Natalia A
  • Langley, Brett C
  • Mahishi, Lata
  • Cooper, Arthur J. L
  • Antonyak, Marc A
  • Cerione, Rick A
  • Li, Bo
  • Starkov, Anatoly
  • Chaturvedi, Rajnish Kumar
  • Beal, M. Flint
  • Coppola, Giovanni
  • Geschwind, Daniel H
  • Ryu, Hoon
  • Xia, Li
  • Iismaa, Siiri E
  • Pallos, Judit
  • Pasternack, Ralf
  • Hils, Martin
  • Fan, Jing
  • Raymond, Lynn A
  • Marsh, J. Lawrence
  • Thompson, Leslie M
  • Ratan, Rajiv R
  • et al.
Abstract

Caused by a polyglutamine expansion in the huntingtin protein, Huntington's disease leads to stnatal degeneration via the transcriptional dysregulation of a number of genes, including those involved in mitochondnal biogenesis. Here we show that transglutaminase 2, which is upregulated in HD, exacerbates transcriptional dysregulation by acting as a selective corepressor of nuclear genes; transglutaminase 2 interacts directly with histone H3 in the nucleus. In a cellular model of HD, transglutaminase inhibition de-repressed two established regulators of mitochondrial function, PGC-l alpha and cytochrome c and reversed susceptibility of human HD cells to the mitochondrial toxin, 3-nitroproprionic acid; however, protection mediated by transglutaminase inhibition was not associated with improved mitochondnal bioenergetics. A gene microarray analysis indicated that transglutaminase inhibition normalized expression of not only mitochondrial genes but also 40% of genes that are dysregulated in HD striatal neurons, including chaperone and histone genes. Moreover, transglutaminase inhibition attenuated degeneration in a Drosophila model of HD and protected mouse HD stnatal neurons from excitotoxicity. Altogether these findings demonstrate that selective TG inhibition broadly corrects transcriptional dysregulation in HD and defines a novel HDAC-independent epigenetic strategy for treating neurodegeneration.

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